Olfactory receptors are encoded by a large family of genes (1,000 in rodents). Olfactory neurons expressing a given receptor are scattered over the epithelium, yet their axons converge on a small number of glomeruli in the olfactory bulb. The bulb is topographically organized, with 1,800 glomeruli representing one thousand olfactory receptors and occupying stereotyped positions. This organization poses a formidable wiring problem: axons of a thousand populations of neurons, distributed over a wide area of the epithelium, have to be connected to 1,800 fixed targets in the bulb. The overall aim of these studies is to unravel this wiring problem in the olfactory system. The hypothesis is that olfactory axons have an innate propensity to form glomeruli. A positional map within the bulb determines the stereotyped sites of convergence of a thousand neuronal subsets. This map is laid down during embryogenesis and may be maintained throughout adult life, because the continuous renewal of the olfactory system requires pathfinding decisions to be taken by newly generated neurons. To test the hypothesis, they will exploit the unique feature of regeneration of the olfactory system. Neurogenesis persists throughout adult life under "normal" laboratory conditions. Experimental lesions result in a more pronounced and synchronized regeneration, which facilitates its investigation. In preliminary studies, the P.I. has lesioned the olfactory system of genetically engineered mice, in which axonal projections of olfactory neurons expressing a given receptor can be visualized as they project from the epithelium to the bulb. The approach is generally based on gene targeting in mouse embryonic stem cells. The specific aims are: Do axons from neurons expressing a given olfactory receptor converge onto discrete locations in the brain when their normal target, the olfactory bulb, is no longer present? After transplantation of an embryonic olfactory bulb, do newly generated neurons expressing a given receptor project their axons to similar locations as before? Does the positional map in the olfactory bulb persist throughout adult life? The health relatedness of the application is that for the brain to function properly, it must be wired properly. Neurons must form specific connections among a vast number of choices. The olfactory system is a uniquely useful model system for neural connectivity. While interesting in their own regard, these studies may help understand the development and plasticity of other neural circuits. New, general, insights may emerge that may be applicable to neurological and psychiatric disorders, particularly those with a developmental etiology.